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Neisseria meningitidis (meningococcus) colonizes the human nasopharynx, primarily as a commensal, but sporadically causing septicemia and meningitis. During colonization and invasion, it encounters different niches with specific nutrient compositions. Small noncoding RNAs (sRNAs) are used to fine-tune expression of genes, allowing adaptation to their physiological differences. We have previously characterized sRNAs ( Neisseria metabolic switch regulators [NmsRs]) controlling switches between cataplerotic and anaplerotic metabolism. Here, we extend the NmsR regulon by studying methylcitrate lyase (PrpF) and propionate kinase (AckA-1) involved in the methylcitrate cycle and serine hydroxymethyltransferase (GlyA) and 3-hydroxyacid dehydrogenase (MmsB) involved in protein degradation. These proteins were previously shown to be dysregulated in a Δ nmsRs strain. Levels of transcription of target genes and NmsRs were assessed by reverse transcriptase quantitative PCR (RT-qPCR). We also used a novel gene reporter system in which the 5' untranslated region (5' UTR) of the target gene is fused to mcherry to study NmsRs-target gene interaction in the meningococcus. Under nutrient-rich conditions, NmsRs downregulate expression of PrpF and AckA-1 by direct interaction with the 5' UTR of their mRNA. Overexpression of NmsRs impaired growth under nutrient-limiting growth conditions with pyruvate and propionic acid as the only carbon sources. Our data strongly suggest that NmsRs downregulate propionate metabolism by lowering methylcitrate enzyme activity under nutrient-rich conditions. Under nutrient-poor conditions, NmsRs are downregulated, increasing propionate metabolism, resulting in higher tricarboxylic acid (TCA) activities. IMPORTANCE Neisseria meningitidis colonizes the human nasopharynx, forming a reservoir for the sporadic occurrence of epidemic invasive meningococcal disease like septicemia and meningitis. Propionic acid generated by other bacteria that coinhabit the human nasopharynx can be utilized by meningococci for replication in this environment. Here, we showed that sibling small RNAs, designated NmsRs, riboregulate propionic acid utilization by meningococci and, thus, colonization. Under conditions mimicking the nasopharyngeal environment, NmsRs are downregulated. This leads to the conversion of propionic acid to pyruvate and succinate, resulting in higher tricarboxylic acid cycle activity, allowing colonization of the nasopharynx. NmsRs link metabolic state with colonization, which is a crucial step on the trajectory to invasive meningococcal disease.

Neisseria meningitidis(the meningococcus) colonizes the human nasopharynx, primarily as a commensal, but sporadically causing septicemia and meningitis. During colonization and invasion, it encounters different niches with specific nutrient compositions. Small non-coding RNAs (sRNAs) are used to fine-tune expression of genes allowing adaptation to their physiological differences. We have previously characterized sRNAs (Neisseria metabolic switch regulators [NmsRs]) controlling switches between cataplerotic and anaplerotic metabolism. Here we extend the NmsRs regulon by studying methylcitrate lyase (PrpF) and propionate kinase (AckA-1) involved in the methylcitrate cycle, and serine hydroxymethyltransferase (GlyA) and 3-hydroxyacid dehydrogenase (MmsB) involved in protein degradation. These proteins were previously shown to be dysregulated in a ΔnmsRsstrain. Levels of transcription of target genes and NmsRs were assessed by RT-qPCR. We also used a novel gene-reporter system, in which the 5’UTR of the target gene is fused to mcherry to study NmsRs-target gene interaction in the meningococcus.Under nutrient-rich conditions, NmsRs downregulate expression of PrpF and AckA-1, by direct interaction with the 5’ UTR of their mRNA. Overexpression of NmsRs impaired growth under nutrient-limiting growth conditions with pyruvate and propionic acid as the only carbon sources. Our data strongly suggest that NmsRs downregulate propionate metabolism by lowering methylcitrate enzyme activity under nutrient-rich conditions. Under nutrient-poor conditions, NmsRs are downregulated, increasing propionate metabolism, resulting in higher tricarboxylic acid (TCA) activities. This allows metabolism to support nasopharynx colonization with breakdown products of amino acids functioning as anaplerotic substrates, as highlighted by NmsRs regulation of GlyA and MmsB.SIGNIFICANCENeisseria meningitidiscolonizes the human adult nasopharynx, forming a reservoir for the sporadic occurrence of epidemic invasive meningococcal disease like septicemia and meningitis. Propionic acid generated by other bacteria that co-inhabit the human adolescent/adult nasopharynx can be utilized by meningococci for replication in this environment. Here we showed that the sibling small RNAs designated NmsRs (Neisseria metabolic switch regulators) riboregulate propionic acid utilization by meningococci, and thus, colonization. Under conditions mimicking the nasopharyngeal environment, NmsRs upregulated expression of enzymes of the methylcitrate cycle. This leads to the conversion of propionic acid to pyruvate and succinate, resulting in higher tricarboxylic acid cycle activity, allowing colonization of the nasopharynx. NmsRs link metabolic state with colonization, which is a crucial step on the trajectory to invasive meningococcal disease.

A decade ago I postulated that ROS formation in mitochondria was influenced by different FADH

International audience; Mitochondria have been fundamental to the eco-physiological success of eukaryotes since the last eukaryotic common ancestor (LECA). They contribute essential functions to eukaryotic cells, above and beyond classical respiration. Mitochondria interact with, and complement, metabolic pathways occurring in other organelles, notably diversifying the chloroplast metabolism of photosynthetic organisms. Here, we integrate existing literature to investigate how mitochondrial metabolism varies across the landscape of eukaryotic evolution. We illustrate the mitochondrial remodelling and proteomic changes undergone in conjunction with major evolutionary transitions. We explore how the mitochondrial complexity of the LECA has been remodelled in specific groups to support subsequent evolutionary transitions, such as the acquisition of chloroplasts in photosynthetic species and the emergence of multicellularity. We highlight the versatile and crucial roles played by mitochondria during eukaryotic evolution, extending from its huge contribution to the development of the LECA itself to the dynamic evolution of individual eukaryote groups, reflecting both their current ecologies and evolutionary histories.

Recently, a review regarding the mechanics and evolution of mitochondrial fission appeared in Nature. Surprisingly, it stated authoritatively that the mitochondrial outer membrane, in contrast with the inner membrane of bacterial descent, was acquired from the host, presumably during uptake. However, it has been known for quite some time that this membrane was also derived from the Gram-negative, alpha-proteobacterium related precursor of present-day mitochondria. The zombie idea of the host membrane still surrounding the endosymbiont is not only wrong, but more importantly, might hamper the proper conception of possible scenarios of eukaryogenesis. Why? Because it steers the imagination not only with regard to possible uptake mechanisms, but also regarding what went on before. Here I critically discuss both the evidence for the continuity of the bacterial outer membrane, the reasons for the persistence of the erroneous host membrane hypothesis and the wider implications of these misconceptions for the ideas regarding events occurring during the first steps towards the evolution of the eukaryotes and later major eukaryotic differentiations. I will also highlight some of the latest insights regarding different instances of endosymbiont evolution.

The number of individuals partaking in veganism has increased sharply in the last decade. Therefore, it is critical to look at the implications of vegan diets for public health. Although there are multiple health benefits of a vegan diet, studies have also linked the diet with deficiencies in various micronutrients. This study focuses on vitamin B12, because of its critical role in DNA synthesis and methylation. In light of these connections, a critical review of recent scientific literature is conducted to understand the effects of a B12 deficient diet on the genome and epigenome, and whether it can give rise to cancer. It is observed that a B12 deficiency leads to increased uracil misincorporation, leading to impaired DNA synthesis and genomic instability. The deficiency also leads to global hypomethylation of DNA, a hallmark of early carcinogenesis. The findings of this study highlight the need for increased awareness among vegans to ensure adequate B12 intake through supplementation or consumption of fortified products as a preventative measure. Additionally, the biofortification of staple crops and an improved version of fermented products with increased B12 content can be developed when inadequate intake seems otherwise inevitable., Percentages of those partaking in veganism are rising. Vegan diets can result in insufficient levels of vitamins, such as B12, critical for DNA synthesis and methylation. Scientific literature shows B12 deficient diets to influence the (epi)genome and thus increase cancer risk. We conclude that vegans should make sure of sufficient B12 intake.

This article describes aspects of our biological nature that have contributed to the dangerous current state of societal, ecological and climatological affairs. Next, it deals with stratagems to take these aspects into account, so as to allow us better choices. I will concentrate on the concepts of evolved group mechanisms and "neoteny" and explain why they direct our responses throughout our lives. The connection between our biological make-up and our vulnerability to the current rise of certain kinds of irrational, undemocratic, populism is also laid bare. I will end by listing some simple, but possibly controversial, proposals that might have value in combating these societal tendencies and help decision making in a reality-based, more scientific, manner.

Though widespread, RNA editing is rare, except in endosymbiotic organelles. A combination of higher mutation rates, relaxation of energetic constraints, and high genetic drift is found within plastids and mitochondria and is conducive for evolution and expansion of editing processes, possibly starting as repair mechanisms. To illustrate this, we present an exhaustive phylogenetic overview of editing types.

Eukaryotic origins are inextricably linked with the arrival of a pre-mitochondrion of alphaproteobacterial-like ancestry. However, the nature of the "host" cell and the mode of entry are subject to heavy debate. It is becoming clear that the mutual adaptation of a relatively simple, archaeal host and the endosymbiont has been the defining influence at the beginning of the eukaryotic lineage; however, many still resist such symbiogenic models. In part 1, it is posited that a symbiotic stage before uptake ("pre-symbiosis") seems essential to allow further metabolic integration of the two partners ending in endosymbiosis. Thus, the author argued against phagocytic mechanisms (in which the bacterium is prey or parasite) as the mode of entry. Such positions are still broadly unpopular. Here it is explained why. Evolutionary thinking, especially in the case of eukaryogenesis, is still dominated by anachronistic reasoning, in which highly derived protozoan organisms are seen as in some way representative of intermediate steps during eukaryotic evolution, hence poisoning the debate. This reasoning reflects a mind-set that ignores that Darwinian evolution is a fundamentally historic process. Numerous examples of this kind of erroneous reasoning are given, and some basic precautions against its use are formulated. Also see the video abstract here https://youtu.be/ekqtNleVJpU.

Obesity and dyslipidaemia are features of the metabolic syndrome and risk factors for chronic kidney disease. The cellular mechanisms connecting metabolic syndrome with chronic kidney disease onset and progression remain largely unclear. We show that proximal tubular epithelium is a target site for lipid deposition upon overnutrition with a cholesterol-rich Western-type diet. Affected proximal tubule epithelial cells displayed giant vacuoles of lysosomal or autophagosomal origin, harbouring oxidised lipoproteins and concentric membrane layer structures (multilamellar bodies), reminiscent of lysosomal storage diseases. Additionally, lipidomic analysis revealed renal deposition of cholesterol and phospholipids, including lysosomal phospholipids. Proteomic profiles of renal multilamellar bodies were distinct from those of epidermis or lung multilamellar bodies and of cytoplasmic lipid droplets. Tubular multilamellar bodies were observed in kidney biopsies of obese hypercholesterolaemic patients, and the concentration of the phospholipidosis marker di-docosahexaenoyl (22:6)-bis(monoacylglycerol) phosphate was doubled in urine from individuals with metabolic syndrome and chronic kidney disease. The enrichment of proximal tubule epithelial cells with phospholipids and multilamellar bodies was accompanied by enhanced inflammation, fibrosis, tubular damage markers, and higher urinary electrolyte content. Concomitantly to the intralysosomal lipid storage, a renal transcriptional response was initiated to enhance lysosomal degradation and lipid synthesis. In cultured proximal tubule epithelial cells, inhibition of cholesterol efflux transport or oxysterol treatment induced effects very similar to the in vivo situation, such as multilamellar body and phospholipid amassing, and induction of damage, inflammatory, fibrotic, and lipogenic molecules. The onset of phospholipidosis in proximal tubule epithelial cells is a novel pathological trait in metabolic syndrome-related chronic kidney disease, and emphasises the importance of healthy lysosomes and nutrition for kidney well-being. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background Susceptibility to pepsin digestion of candidate transgene products is regarded an important parameter in the weight-of-evidence approach for allergenicity risk assessment of genetically modified crops. It has been argued that protocols used for this assessment should better reflect physiological conditions encountered in representative food consumption scenarios. Aim To evaluate whether inclusion of more physiological conditions, such as sub-optimal and lower pepsin concentrations, in combination with pancreatin digestion, improved the performance of digestibility protocols used in characterization of protein stability. Methods Four pairs of established allergens and their related non/weakly-allergenic counterparts (seed albumins, muscle tropomyosins, plant lipid transfer proteins [LTP] and collagens) plus fish parvalbumin, were subjected to nine combinations of pH (1.2–2.5–4.0) and pepsin-to-protein ratio (PPR: 10–1–0.1 U/µg) for pepsin digestion, followed by pancreatin digestion in the presence of bile salts. Digestion was monitored by SDS-PAGE in conjunction with Coomassie staining and immunoblotting using rabbit antisera and human IgE. Results At pH 4.0 and at PPR 0.1 most proteins, both allergen and non-allergen, were highly resistant to pepsin. Under conditions known to favor pepsin proteolysis, the established major allergens Ara h 2, Pru p 3 and Pen a 1 were highly resistant to proteolysis, while the allergen Cyp c 1 was not. However, this resistance to pepsin digestion only made Ara h 2 and to a lesser extent Pen a 1 and Pru p 3 stand out compared to their non-allergenic counterparts. Largely irrespective of preceding pepsin digestion conditions, pancreatin digestion was very effective for all tested proteins, allergens and non-allergens, except for Cyp c 1 and bovine collagen. Conclusions Sub-optimal pH, low pepsin-to protein ratio, and sequential pepsin and pancreatin digestion protocols do not improve the predictive value in distinguish allergens from non-allergens. Digestion conditions facilitating such distinction differ per protein pair. Electronic supplementary material The online version of this article (10.1186/s13601-018-0216-9) contains supplementary material, which is available to authorized users.

Most patients with acute myeloid leukemia (AML) can only be cured when allogeneic hematopoietic stem-cell transplantation induces a graft-versus-leukemia immune response (GVL). Although the role of T cells and natural killer cells in tumor immunology has been established, less is known about the contribution of B cells. From B cells of high-risk patients with AML with potent and lasting GVL responses, we isolated monoclonal antibodies directed against antigens expressed on the cell surface of AML cells but not on normal hematopoietic and nonhematopoietic cells. A number of these donor-derived antibodies recognized the U5 snRNP200 complex, a component of the spliceosome that in normal cells is found in the cell. In AML however, the U5 snRNP200 complex is exposed on the cell membrane of leukemic blasts. U5 snRNP200 complex-specific antibodies induced death of AML cells in an Fc receptor-dependent way in the absence of cytotoxic leukocytes or complement. In an AML mouse model, treatment with U5 snRNP200 complex-specific antibodies led to significant tumor growth inhibition. Thus, donor-derived U5 snRNP200 complex-recognizing AML-specific antibodies may contribute to antitumor responses.

The conserved RNA-binding protein, Hfq, has multiple regulatory roles within the prokaryotic cell, including promoting stable duplex formation between small RNAs and mRNAs, and thus hfq deletion mutants have pleiotropic phenotypes. Previous proteome and transcriptome studies of Neisseria meningitidis have generated limited insight into differential gene expression due to Hfq loss. In this study, reversed-phase liquid chromatography combined with data-independent alternate scanning mass spectrometry (LC-MSE) was utilized for rapid high-resolution quantitative proteomic analysis to further elucidate the differentially expressed proteome of a meningococcal hfq deletion mutant. Whole-cell lysates of N. meningitidis serogroup B H44/76 wild-type (wt) and H44/76 Delta hfq (Delta hfq) grown in liquid growth medium were subjected to tryptic digestion. The resulting peptide mixtures were separated by liquid chromatography (LC) prior to analysis by mass spectrometry (MSE). Differential expression was analyzed by Student's t-test with control for false discovery rate (FDR). Reliable quantitation of relative expression comparing wt and Delta hfq was achieved with 506 proteins (20%). Upon FDR control at q

NrrF is a small regulatory RNA of the human pathogen Neisseria meningitidis. NrrF was previously shown to repress succinate dehydrogenase (sdhCDAB) under control of the ferric uptake regulator (Fur). Here, we provide evidence that cytochrome bc 1, encoded by the polycistronic mRNA petABC, is a NrrF target as well. We demonstrated differential expression of cytochrome bc 1 comparing wild‐type meningococci and meningococci expressing NrrF when sufficient iron is available. Using a gfp‐reporter system monitoring translational control and target recognition of sRNA in Escherichia coli, we show that interaction between NrrF and the 5′ untranslated region of the petABC mRNA results in its repression. The NrrF region essential for repression of petABC was identified by site‐directed mutagenesis and is fully conserved among meningococci. Our results provide further insights into the mechanism by which Fur controls essential components of the N. meningitidis respiratory chain. Adaptation of cytochrome bc 1 complex component levels upon iron limitation is post‐transcriptionally regulated via the small regulatory RNA NrrF.

Eukaryotic origins are heavily debated. The author as well as others have proposed that they are inextricably linked with the arrival of a pre-mitochondrion of alphaproteobacterial-like ancestry, in a so-called symbiogenic scenario. The ensuing mutual adaptation of archaeal host and endosymbiont seems to have been a defining influence during the processes leading to the last eukaryotic common ancestor. An unresolved question in this scenario deals with the means by which the bacterium ends up inside. Older hypotheses revolve around the application of known antagonistic interactions, the bacterium being prey or parasite. Here, in reviewing the field, the author argues that such models share flaws, hence making them less likely, and that a "pre-symbiotic stage" would have eased ongoing metabolic integration. Based on this the author will speculate about the nature of the (endo) symbiosis that started eukaryotic evolution-in the context of bacterial entry being a relatively "early" event-and stress the differences between this uptake and subsequent ones. He will also briefly discuss how the mutual adaptation following the merger progressed and how many eukaryotic hallmarks can be understood in light of coadaptation. Also see the video abstract here https://youtu.be/ekqtNleVJpU.

Background The latent HIV-1 reservoir in treated patients primarily consists of resting memory CD4+ T cells. Stimulating the T-cell receptor (TCR), which facilitates transition of resting into effector T cells, is the most effective strategy to purge these latently infected cells. Here we supply evidence that TCR-stimulated effector T cells still frequently harbor latent HIV-1. Methods Primary HIV-1 infected cells were used in a latency assay with or without dendritic cells (DCs) and reversion of HIV-1 latency was determined, in the presence or absence of specific pathway inhibitors. Findings Renewed TCR-stimulation or subsequent activation with latency reversing agents (LRAs) did not overcome latency. However, interaction of infected effector cells with DCs triggered further activation of latent HIV-1. When compared to TCR-stimulation only, CD4+ T cells from aviremic patients receiving TCR + DC-stimulation reversed latency more frequently. Such a “one-two punch” strategy seems ideal for purging the reservoir. We determined that DC contact activates the PI3K-Akt-mTOR pathway in CD4+ T cells. Interpretation This insight could facilitate the development of a novel class of potent LRAs that purge latent HIV beyond levels reached by T-cell activation.

Reading Venki Ramakrishnan's "Gene Machine", describing the race to decipher the structure of the ribosome, inspired thoughts on the power of the internet: mostly for good in science, but often detrimental to society. Why is this so? The non-ideological nature of science holds part of the answer.

The number of individuals partaking in veganism has increased sharply in the last decade. Therefore, it is critical to look at the implications of vegan diets for public health. Although there are multiple health benefits of a vegan diet, studies have also linked the diet with deficiencies in various micronutrients. This study focuses on vitamin B12, because of its critical role in DNA synthesis and methylation. In light of these connections, a critical review of recent scientific literature is conducted to understand the effects of a B12 deficient diet on the genome and epigenome, and whether it can give rise to cancer. It is observed that a B12 deficiency leads to increased uracil misincorporation, leading to impaired DNA synthesis and genomic instability. The deficiency also leads to global hypomethylation of DNA, a hallmark of early carcinogenesis. The findings of this study highlight the need for increased awareness among vegans to ensure adequate B12 intake through supplementation or consumption of fortified products as a preventative measure. Additionally, the biofortification of staple crops and an improved version of fermented products with increased B12 content can be developed when inadequate intake seems otherwise inevitable.

Reactive oxygen species (ROS) formation by mitochondria is an incompletely understood eukaryotic process. I proposed a kinetic model [BioEssays (2011) 33, 88–94] in which the ratio between electrons entering the respiratory chain via FADH2 or NADH (the F/N ratio) is a crucial determinant of ROS formation. During glucose breakdown, the ratio is low, while during fatty acid breakdown, the ratio is high (the longer the fatty acid, the higher is the ratio), leading to higher ROS levels. Thus, breakdown of (very-long-chain) fatty acids should occur without generating extra FADH2 in mitochondria. This explains peroxisome evolution. A potential ROS increase could also explain the absence of fatty acid oxidation in long-lived cells (neurons) as well as other eukaryotic adaptations, such as dynamic supercomplex formation. Effective combinations of metabolic pathways from the host and the endosymbiont (mitochondrion) allowed larger varieties of substrates (with different F/N ratios) to be oxidized, but high F/N ratios increase ROS formation. This might have led to carnitine shuttles, uncoupling proteins, and multiple antioxidant mechanisms, especially linked to fatty acid oxidation [BioEssays (2014) 36, 634–643]. Recent data regarding peroxisome evolution and their relationships with mitochondria, ROS formation by Complex I during ischaemia/reperfusion injury, and supercomplex formation adjustment to F/N ratios strongly support the model. I will further discuss the model in the light of experimental findings regarding mitochondrial ROS formation.

Summary: Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function. : The link between systemic and cellular metabolism is a neglected aspect in immunometabolism. Baardman et al. show that hypercholesterolemia alters macrophage metabolism and phenotype. The suppressed pentose phosphate pathway (PPP) in those “foam cell” macrophages attenuates inflammatory responses, signifying that systemic and cellular metabolism together regulate macrophage function. Keywords: immunometabolism, inflammation, macrophages, hypercholesterolemia, pentose phosphate pathway, Nrf2, meta-inflammation, foam cells, atherosclerosis, cardiovascular disease, metabolic disease

Aspects of peroxisome evolution, uncoupling, carnitine shuttles, supercomplex formation, and missing neuronal fatty acid oxidation (FAO) are linked to reactive oxygen species (ROS) formation in respiratory chains. Oxidation of substrates with high FADH

Summary Activation of macrophages by inflammatory stimuli induces reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines and nitric oxide. Hallmarks of this metabolic rewiring are downregulation of α-ketoglutarate formation by isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the nuclear receptor Nur77 (Nr4a1) as a key upstream transcriptional regulator of this pro-inflammatory metabolic switch in macrophages. Nur77-deficient macrophages fail to downregulate IDH expression and accumulate higher levels of succinate and other TCA cycle-derived metabolites in response to inflammatory stimulation in a glutamine-independent manner. Consequently, these macrophages produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis development and leads to increased circulating succinate levels. In summary, Nur77 induces an anti-inflammatory metabolic state in macrophages that protects against chronic inflammatory diseases such as atherosclerosis., Graphical Abstract, Highlights • Genome-wide profiling indicates that Nur77 regulates macrophage mitochondrial metabolism • Nur77 inhibits IDH expression and TCA cycle activity in inflammatory macrophages • Nur77-deficient macrophages produce more nitric oxide and cytokines via SDH • Nur77 deficiency increases circulating succinate levels and atherosclerosis in vivo, Koenis et al. show that nuclear receptor Nur77 regulates the reprogramming of mitochondrial metabolism in inflammatory macrophages. Nur77-deficient macrophages accumulate higher levels of succinate and produce more pro-inflammatory cytokines and nitric oxide in a succinate dehydrogenase-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis and increases circulating succinate levels.

How did full meiotic eukaryotic sex evolve and what was the immediate advantage allowing it to develop? We propose that the crucial determinant can be found in internal reactive oxygen species (ROS) formation at the start of eukaryotic evolution approximately 2 × 10 9 years ago. The large amount of ROS coming from a bacterial endosymbiont gave rise to DNA damage and vast increases in host genome mutation rates. Eukaryogenesis and chromosome evolution represent adaptations to oxidative stress. The host, an archaeon, most probably already had repair mechanisms based on DNA pairing and recombination, and possibly some kind of primitive cell fusion mechanism. The detrimental effects of internal ROS formation on host genome integrity set the stage allowing evolution of meiotic sex from these humble beginnings. Basic meiotic mechanisms thus probably evolved in response to endogenous ROS production by the ‘pre-mitochondrion’. This alternative to mitosis is crucial under novel, ROS-producing stress situations, like extensive motility or phagotrophy in heterotrophs and endosymbiontic photosynthesis in autotrophs. In multicellular eukaryotes with a germline–soma differentiation, meiotic sex with diploid–haploid cycles improved efficient purging of deleterious mutations. Constant pressure of endogenous ROS explains the ubiquitous maintenance of meiotic sex in practically all eukaryotic kingdoms. Here, we discuss the relevant observations underpinning this model.